Recently, the number of those who have a risk factor considered to cause heart diseases, such as smoking, hypertension, hyperglycemia, and hyperlipidemia, have increased in some countries. There is an increasing trend in the number of patients suffering from heart failure. In addition, these pathologic states are not limited to human and the increasing trend in morbidity of such diseases are seen among animals that closely interact with human, such as dogs, cats, other companion animals and pet animals.
Since the pathologic state, classification, and progression of heart failure varies, the disease cannot be readily defined. Yet it can be roughly divided into two types: systolic heart failure and diastolic heart failure. In some cases, these two types simultaneously occur. Systolic heart failure occurs when the heart fails to contract normally. The heart can take in blood but cannot fully pump out adequate blood due to weakened cardiac muscles. As a result, the volume of the blood pumping out to the whole body and lungs decreases and the heart, in particular the left ventricle, can become hypertrophic. On the other hand, diastolic heart failure occurs when the heart wall becomes too stiff to fill up the heart with blood. As a result, blood dams up in the left atrium and lung blood vessels, which could cause congestion. Thus, heart failure generally refers to a condition that heart's pump functions become impaired and hence the heart become incapable of pumping a sufficient amount of blood. Heart failure could cause other changes which further deteriorate functions of the heart, including a decrease in blood volume and congestion of blood in the veins and lungs.
Examples of primary diseases that may cause heart failure include increased pressure overload by hypertension, aortostenosis and the like, cardiac hypertrophy with heart wall thickening by volume overload and the like by valvular disease. Meanwhile, after the onset of myocardial infarction, heart wall thickening may be developed in injury tissues as a spontaneous reaction for functional recovery. Also, agnogenic myocardiopathy of unexplained origins, such as myocardosis, may also cause heart wall hypertrophy. Continuous mechanical load to the heart triggers a gradual decrease in the contractile power of the cardiac muscles, followed by reduction in cardiac performance, and eventually progresses to ventricular arrhythmia, heart ischemia, coronary artery disease, and congestive heart failure.
Considering the situation, a compound having the suppressive action against heart wall thickening is useful for prophylaxis and treatment of cardiac hypertrophy and heart failure.
As a method for improving heart wall thickening, in the case of cardiac hypertrophy caused by hypertension and the like, for instance, treating stem-cause hypertension can improve heart wall thickening in some cases. However, the action is not satisfactory and also some antihypertensive drugs have no effects (Am J Hypertens. 1997 August; 10(8):913˜20). Also, even when hypertension is improved, heart wall thickening remains unimproved in many cases. In such cases there is still a risk for the onset of heart failure.
Effective drugs for treating heart failure include angiotensin converting enzyme inhibitors (ACEI), such as Enalapril, which inhibits an enzyme converting angiotensin I to angiotensin II having a hypertensive action (i.e. angiotensin converting enzyme; ACE), and has a hypotensive action. In addition, the antihypertensive drug reportedly improves the progression of renal damage at the same time as lowering blood pressure (J. Clin. Invest., 77, 1993-2000, 1986). Yet on the other hand, for heart failure induced by various primary diseases, the ACE inhibitors are not effective for all cases. Rather there is a risk of developing acute renal failure accompanying lowering blood pressure and therefore it has been pointed out that careful administration is required (Saishin Igaku, 48:1404 to 1409, 1993). That is, the antihypertensive drug can be insufficient for the prophylaxis of heart failure but also could rather induce renal failure.
Meanwhile, it has been reported that a peptide originated from food materials, such as casein has the ACE inhibitory activity and such peptides are known to have a hypotensive action. However, whether they have a suppressive action against heart wall thickening or not has not been directly demonstrated (Japanese Patent Publication No. 2782142, J. Dairy Sci. 1995, 78:777-78, J. Dairy Sci. 1995, 78:1253-1257, Am. J. Clin. Nutr. 1996, 64:767-771). Additionally, as described above, since the prophylactic and therapeutic effect for heart failure mediated by ACE inhibition is limited, prophylaxis and treatment of the disease which are not dependent on the ACE inhibition are desired.